Condensed imidazopyridine derivatives useful as psychotropic agents

ABSTRACT

A compound of the formula: ##STR1## (wherein R is phenyl optionally substituted by one or two members selected from the group consisting of trifluoromethyl, C 1  -C 5  alkyl, C 1  -C 5  alkoxy, C 1  -C 5  alkylthio, nitro, amino C 1  -C 5  alkanoylamino and C 1  -C 5  alkoxycarbonyl or 5- or 6-membered heterocyclic group optionally substituted by one or two members selected from the group consisting of halogen, C 1  -C 5  alkyl and C 1  -C 5  alkoxy, 
     Q is hydrogen, C 1  -C 5  alkyl, C 1  -C 10  acyl, C 1  -C 5  alkylsulfonyl or C 6  -C 10  arylsulfonyl, ##STR2## R 1 , R 2 , R 3 , and R 4  each is hydrogen, halogen C 1  -C 5  alkyl, C 1  -C 5  alkoxy or C 1  -C 5  haloalkyl, 
     Q is present on the nitrogen atom of the 1,3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5 / 1, 3b; 2, 3; 3a, 4 / or 1, 2; 3a, 3b; 4, 5) 
     or its salt, being useful as psychostimulants or anxiolytics, is provided.

The present invention relates to condensed imidazopyridine derivatives. More particularly, this invention is directed to condensed imidazopyridine derivatives which have been found to be particularly effective in the treatment of depression or anxiety, to their preparation, to their use and to pharmaceutical formulations containing the compounds.

USSR Pat. No. 509,588 discloses that 1H-2-oxo-3-phenyl-7-methylimidazo[4,5-c]quinoline is useful as a synthetic intermediate to biologically active materials. Abbasi et al, [Monatsh. Chem., 111, 963 (1980)] disclose 3-hydroxy-2-hydroxymethyl-8-methoxy-9-nitro-4-styryl-2H-imidazo[4,5-c]quinoline and its analogs as synthetic intermediates to biologically active materials. Further European Pat. Appln. No. 145,340 describes 2-hydroxyalkyl-1H-imidazo[4,5-c]quinolines useful as bronchodilators or antiviral agents.

The condensed imidazopyridine derivatives of the present invention are those having at 2-position phenyl optionally substituted by one or two members selected from the group consisting of trifluoromethyl, C₁ -C₅ alkyl, C₁ -C₅ alkoxy, C₁ -C₅ alkylthio, nitro, amino, C₁ -C₅ alkanoylamino and C₁ -C₅ alkoxycarbonyl, or 5- or 6-membered heterocyclic group optionally substituted by one or two members selected from the group consisting of halogen, C₁ -C₅ alkyl and C₁ -C₅ alkoxy and are therefore quite different from the compounds disclosed in the above references.

According to the present invention there is provided a condensed imidazopyridine derivative of the formula: ##STR3## (wherein R is phenyl optionally substituted by one or two members selected from the group consisting of trifluoromethyl, C₁ -C₅ alkyl, C₁ -C₅ alkoxy, C₁ -C₅ alkylthio, nitro, amino, C₁ -C₅ alkanoylamino and C₁ -C₅ alkoxycarbonyl, or 5- or 6-membered heterocyclic group optionally substituted by one or two members selected from the group consisting of halogen, C₁ -C₅ alkyl and C₁ -C₅ alkoxy, Q is hydrogen, C₁ -C₅ alkyl, C₁ -C₁₀ acyl, C₁ -C₅ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl, ##STR4## R¹, R², R³ and R⁴ each is hydrogen, halogen, C₁ -C₅ alkyl, C₁ -C₅ alkoxy or C₁ -C₂ haloalkyl, Q is present on the nitrogen atom of the 1, 3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5/1, 3b; 2, 3; 3a, 4/or 1, 2; 3a, 3b; 4, 5) or its salt.

The compounds of the present invention have an excellent psychotropic activity such as psychostimulant or anxiolytic activity with no undesirable action to the human beings. Accordingly, the invention also provides a psychotropic formulation comprising as an active ingredient 0.1 to 95% by weight of a compound of the formula (I) associated with at least one carrier, diluent or excipient therefor.

This invention also provides a method of treating a patient suffering from depression or anxiety which comprises administering to the patient a pharmacologically effective amount of a compound of the formula (I).

This invention further provides a process for preparing a compound of the formula (I) which comprises reacting a compound of the formula: ##STR5## (wherein Q' is hydrogen or C₁ -C₅ alkyl, and ##STR6## is as defined above) with an acylating agent to give a compound of the formula: ##STR7## (wherein ##STR8## and Q' each is as defined above) and cyclizing the compound (III) and when Q' is hydrogen, applying the cyclized product to alkylation, acylation or sulfonylation, if necessary.

The term "C₁ -C₅ alkyl" herein employed refers to a straight or branched saturated aliphatic hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or 1-methylisobutyl.

The term "C₁ -C₅ alkoxy" refers to an alkoxy group containing C₁ -C₅ alkyl moiety and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy.

The term "C₁ -C₅ alkylthio" refers to an alkylthio group containing C₁ -C₅ alkyl moiety and includes methylthio, ethylthio, propylthio, butylthio isobutylthio and neopentylthio.

The term "C₁ -C₅ alkanoylamino" includes formylamino, acetylamino, propionylamino, butyrylamino, valerylamino and isovalerylamino.

The term "C₁ -C₅ alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl.

The term "5- or 6-membered heterocyclic group" includes isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl and pyridyl.

The term "C₁ -C₁₀ acyl" includes C₁ -C₅ alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl or isovaleryl and C₇ -C₁₁ aroyl such as benzoyl, toluoyl or propylbenzoyl.

The term "C₁ -C₅ alkylsulfonyl" includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isobutylsulfonyl and pentylsulfonyl.

The term "C₆ -C₁₀ arylsulfonyl" includes phenylsulfonyl, tolylsulfonyl, xylylsulfonyl and naphthylsulfonyl.

The term "C₁ -C₅ haloalkyl" includes fluoromethyl, chloroethyl, bromopropyl, iodobutyl and trifluoromethyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The process for preparing the compound (I) is shown by the scheme as follows: ##STR9## (wherein Q' is hydrogen or C₁ -C₅ alkyl, and ##STR10## Q and R are as defined above).

Step (1)

The amide (III) can be prepared by reacting the diamine (II) with an acylating reagent. The reaction is performed at a comparatively lower temperarture (e.g. -10° to 5° C.) generally in an appropriate solvent, using an acylating agent containing a necessary acyl group. The solvent includes illustratively dimethylformamide, acetonitrile, chloroform, hexamethylphosphoramide, ether, tetrahydrofuran and mixtures thereof. The acylating reagent refers to an acid halogenide such as acid chloride or acid bromide; a mixed acid anhydride; a mixture of carboxylic acid with thionyl chloride; a mixture of carboxylic acid with a condensing agent such as DCC or polyphosphoric acid.

Step (2)

The compound (Ia) can be prepared by heating the amide (III) in a solvent at a temperature from about 50° C. to 250° C., preferably 100° C. to 250° C. in the presence or absence of a cyclizing agent such as polyphosphoric acid, polyphosphoric ester, sulfuric acid, acetic acid or phosphorus pentoxide. The solvent includes illustratively hexamethylphosphoramide, diphenyl ether, glycerin triethyl ether, butyl ether, isoamyl ether, diethylene glycol, triethylene glycol or Dowtherm A (Dow Chemical Co.).

Step (3)

As necessary, the compound (Ia) (Q'=Hydrogen) may be subjected to alkylation, acylation or sulfonylation. The reaction is performed with an alkylating, acylating or sulfonylating agent in an appropriate solvent in the presence of a base such as alkali metal hydride. (e.g. sodium hydride, potassium hydride) or alkali metal alkoxide (e.g. sodium methoxide, potassium ethoxide, sodium isopropoxide) at a temperature of 30° to 120° C. The alkylating agent includes alkyl halide such as methyl iodide, ethyl bromide, propyl chloride or butyl iodide and dialkyl sulfate such as dimethyl sulfate or diethyl sulfate. The acylating agent includes acyl halide such as acetyl chloride, propionyl bromide, butyryl chloride or benzoyl chloride and acid anhydride such as acetic anhydride or propionic anhydride. The sulfonylating agent includes mesyl chloride, butylsulfonyl chloride and tosyl chloride. As solvents there are exemplified tetrahydrofuran, dioxane, diglyme, dimethylformamide, chloroform and ethanol.

The diamine (II) usable as a starting material can be prepared, as shown below, in accordance with the methods of G. B. Bachman et al., J. Am. Chem. Soc., 69, 365 (1947) and A. R. Surrey et al., J. Am. Chem. Soc., 73, 2413 (1951). ##STR11## (wherein Ac is acetyl; ##STR12## and Q' are as defined above.) The compound (I) includes the following three compounds (Ia, Ib and Ic): ##STR13## (wherein ##STR14## Q' and R are as defined above).

The compound (I) can be converted into its pharmaceutically acceptable acid addition salts. Such acids illustratively include an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid and an organic acid such as acetic acid, maleic acid, malic acid, citric acid, lactic acid, succinic acid or methanesulfonic acid.

The compounds (I) or pharmaceutically acceptable acid addition salts thereof have a high affinity to a benzodiazepine receptor, and they are useful as psychotropic agents such as psychostimulants or anxiolytics.

The compounds (I) can be administered orally or parenterally to human beings or other animals. They can be formulated as tablets, capsules, pills, granules, injections, suppositories, and syrups in pharmaceutical practice. As pharmaceutically acceptable carriers, diluents or excipients there are exemplified lactose, sucrose, wheat starch, potato starch, magnesium stearate, gelatin, methyl cellulose, agar, water, and the like. As necessary, appropriate stabilizers, emulsifiers, spreaders, buffers and other pharmaceutical adjuvants can be added. Appropriate daily dosage of the compound (I) is 0.1 to 500 mg in oral route and 0.1 to 300 mg in injection.

The present invention will be explained in more detail by the following Examples, Referential Examples and Formulations.

The abbreviations used in Examples, Referential Examples and Tables have the following meanings.

HMPA: Hexamethylphosphoramide

Me: Methyl

Et: Ethyl

PPA: Polyphosphoric acid

MeCN: Acetonitrile

MeOH: Methanol

EtOH: Ethanol

Et₂ O: Ether

AcOEt: Ethyl acetate

AcOH: Acetic acid

DMF: Dimethylformamide

(d): Decomposition

When Q is hydrogen, the compound (Ia) and (Ib) being a tautomer each other will be named conveniently as said formula (Ia).

For example, 2-(3-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₁ (Example 1) may also be named as 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-c]quinoline.

EXAMPLE 1 2-(3-Trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₁ ##STR15##

To a solution of 500 mg of 3-trifluoromethylbenzoic acid in 6 ml of anhydrous hexamethylphosphoramide (HMPA) and 0.6 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 380 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water, and dried to give 780 mg of 4-amino-3-(3-trifluoromethylbenzoylamino)quinoline B₁ as a crude product. It is suspended in 15 g of polyphosphoric acid and heated at 120° C. for 4 hours with stirring. The mixture is poured into ice-water and neutralized with 1N sodium hydroxide. The resulting solid is filtered, washed with water and dried. It is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent, yielding 350 mg (47%) of C₁ as colorless crystals.

m.p. 254°-256° C. (from ethyl acetate).

Anal. Calcd.(%) (for C₁₇ H₁₀ N₃ F₃): C, 65.18; H, 3.22; N, 13.41; F, 18.19. Found (%): C, 64.74; H, 3.54; N, 13.20; F, 18.30.

EXAMPLE 2-3

According to the method illustrated by Example 1, the compounds C₂ and C₃ are prepared under the conditions shown in Table 1. Table 3 shows the physical properties of these compounds.

                                      TABLE 1                                      __________________________________________________________________________      ##STR16##                                                                      ##STR17##                                                                     __________________________________________________________________________                   Step (1)                                                                                     HMPAMeCN   Compd.                                                                               Reaction                          Ex. No.                                                                             R        RCO.sub.2 H (mg)                                                                      SOCl.sub.2 (mg)                                                                       (ml) (ml)  A.sub.1 (mg)                                                                         Time (hr)                         __________________________________________________________________________           ##STR18##                                                                              420    305    6    0.6   380   3.5                               3                                                                                    ##STR19##                                                                              370    305    6    0.6   380   3.5                               __________________________________________________________________________                   Step (2)                                                                                         Compd. C                                                                 Reaction    Yield (%)                                Ex. No.                                                                             R        PPA (g)                                                                             Temp. (°C.)                                                                    Time (hr)                                                                            Yield (mg)                                                                           from A.sub.1                                                                         Compd. No.                         __________________________________________________________________________           ##STR20##                                                                              15   120    7.5   365   54    C.sub.2                            3                                                                                    ##STR21##                                                                              12   135    4     480   76    C.sub.3                            __________________________________________________________________________

EXAMPLE 4 2-(5-Methylthien-2-yl)-1H-imidazo[4,5-c]quinoline C₄ ##STR22##

To a solution of 555 mg of 5-methylthiophene-2-carboxylic acid in 9 ml of anhydrous hexamethylphosphoramide and 0.9 ml of anhydrous acetonitrile is added dropwise 455 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 570 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 4 hours. The same work-up as described in Example 1 gives 900 mg of 4-amino-3-(5-methylthien-2-ylcarbonylamino)quinoline B₄ as a white solid. It is suspended in 15 g of polyphosphate ester and heated at 125° C. with stirring for 3 hours. The mixture is diluted with ice-water and neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent to give 456 mg (48%) of C₄ as pale yellow crystals.

m.p. 293°-295° C. (dec.) (from ethanol).

Anal. Calcd. (%) (for C₁₅ H₁₁ N₃ S): C, 67.90; H, 4.18; N, 15.84; S, 12.08. Found (%): C, 68.16; H, 4.25; N, 15.76; S, 11.63.

EXAMPLE 5 2-(Pyridin-4-yl)-1H-imidazo[4,5-c]quinoline C₅ ##STR23##

To a solution of 325 mg of isonicotinic acid in 8 ml of anhydrous hexamethylphosphoramide and 0.8 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring for 45 minutes, 380 mg of 3,4-diaminoquinoline A₁ is added and the mixture is stirred at 0° C. for 4.5 hours. The same work-up as described in Example 1 gives 560 mg of crude crystals of B₅. It is dissolved in 10 ml of acetic acid and refluxed for 4 hours. The mixture is concentrated under reduced pressure and mixed with ice-water and neutralized with saturated sodium bicarbonate. The resulting crystals are filtered and dried to yield 510 mg (87%) of C₅ as white crystals.

m.p. 270°-272° C. (from ethyl acetate-methanol).

Anal. Calcd.(%) (for C₁₅ H₁₀ N₄): C, 73.16; H, 4.09; N, 22.75. Found (%): C, 72.79; H, 4.20; N, 22.37.

EXAMPLE 6 2-(4-Trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₆ ##STR24##

To a solution of 395 mg of 4-trifluoromethylbenzoic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 240 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 300 mg of 3,4-diaminoquinoline A₁ is added and stirred at 0°-5° C. for 4 hours. The same work-up as described in Example 1 gives 605 mg of the crude crystals of B₆. It is suspended in 10 ml of hexamethylphosphoramide and 2.5 ml of acetic acid, and stirred at 155° C. for 15 minutes under nitrogen. The cooled mixture is diluted with water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent to give 440 mg (75% of C₆ as white crystals.

m.p.: >340° C. (from ethanol).

Anal. Calcd. (%) (for C₁₇ H₁₀ N₃ F₃): C, 65.18; H, 3.22; N, 13.41; F, 18.19. Found (%): C, 64.95; H, 3.44; N, 13.24; F, 18.10.

EXAMPLE 7-93

According to the method illustrated by Example 6, Compounds C₇ -C₉₃ are prepared under the conditions shown in Table 2. Table 3 shows the physical properties of these compounds.

    TABLE 2       ##STR25##        Step (1) Step (2) Compd. C        Reaction   Reaction  Yield  Ex.      RCO.sub.2 H SOCl.sub.2 HMPAMeCN  Compd. time HMPAAcOH Temp. Time Yield      (%) from Compd. No. R (mg) (mg) (ml) (ml) R.sup.1 R.sup.2 (mg) (hr) (ml) (      ml) (°C.) (min) (mg) Compd. A No.       7      ##STR26##       670 710 12 1.2 H H 760 3.5 20 5 155 100  875 73 C.sub.7       8      ##STR27##       520 305 6 0.6 H H 380 3.5 12 3 150 35 560 73 C.sub.8       9      ##STR28##       420 305 6 0.6 H H 380 4.5 12 3 155 30 390 57 C.sub.9       10      ##STR29##       325 305 6 0.6 H H 380 4.5 2 4 140 120  315 53 C.sub.10       11      ##STR30##       335 305 6 0.6 H H 380 4.5 10 2.5 150 30 365 61 C.sub.11       12      ##STR31##       295 305 6 0.6 H H 380 4.5 2 4 140 120  210 37 C.sub.12       13      ##STR32##       315 240 5 0.5 H H 300 4.5 8 2 150 30 230 44 C.sub.13       14      ##STR33##       320 305 6 0.6 H H 380 3.5 10 2.5 145 15 430 13 C.sub.14       15      ##STR34##       280 200 5 0.5 6-Cl H 300 4.5 8 2 150 60 270 54 C.sub.15       16      ##STR35##       240 200 5 0.5 6-Cl H 300 4.5 8 2 155 30 275 60 C.sub.16       17      ##STR36##       295 305 6 0.6 H H 380 4.5 10 2.5 150 30 320 60 C.sub.17       18      ##STR37##       350 240 5 0.5 H H 300 4.5 8 2 150 30 340 62 C.sub.18       19      ##STR38##       370 240 5 0.5 H H 300 4.5 10 2.5 150 15 375 66 C.sub.19       20      ##STR39##       290 240 5 0.5 H H 300 4.5 8 2 165 15 330 67 C.sub.20       21      ##STR40##       290 240 5 0.5 H H 300 4.5 4 4 150 90 350 71 C.sub.21       22      ##STR41##       325 240 5 0.5 H H 300 4.5 8 2 155 45 310 59 C.sub.22       23      ##STR42##       330 240 5 0.5 H H 300 4.5 8 2 165 30 380 71 C.sub.23       24      ##STR43##       315 240 5 0.5 H H 300 4.5 12 4 165 60 370 71 C.sub.24       25      ##STR44##       380 305 6 0.6 H H 380 4.5 10 2.5 155 10 350 55 C.sub.25       26      ##STR45##       375 240 5 0.5 H H 300 4.5 12 3 155 30 255 45 C.sub.26       27      ##STR46##       425 305 6 0.5 H H 380 4.5 8 2 155 10 520 77 C.sub.27       28      ##STR47##       380 240 5 0.5 H H 300 3.5 8 2 165 30 280 49 C.sub.28       29      ##STR48##       380 240 5 0.5 H H 300 3.5 8 2 165 20 390 68 C.sub.29       30      ##STR49##       350 240 5 0.5 H H 300 5.5 10 2.5 165 60 460 84 C.sub.30       31      ##STR50##       330 240 5 0.5 H H 300 4.5 4 4 145 45 480 91 C.sub.31       32      ##STR51##       330 240 5 0.5 H H 300 4.5 4 4 140 30 470 89 C.sub.32       33      ##STR52##       330 240 5 0.5 H H 300 3.5 6 4 155 30 430 81 C.sub.33       34      ##STR53##       465 305 6 0.6 H H 380 4.5 10 0 225 30 565 79 C.sub.34        35      ##STR54##       265 240 5 0.5 7-Cl H 365 4.5 8 2 160 30 380 71 C.sub.35       36      ##STR55##       290 240 5 0.5 7-Cl H 365 4.5 8 2 160 15 385 69 C.sub.36       37      ##STR56##       375 305 6 0.5 H H 380 4.5 10 2.5 160 45 540 85 C.sub.37       38      ##STR57##       295 240 5 0.5 7-Cl H 365 4.5 8 2 165 40 400 71 C.sub.38       39      ##STR58##       295 240 5 0.5 7-Cl H 365 4.5 8 2 170 10 380 67 C.sub.39       40      ##STR59##       290 240 5 0.5 6-F H 330 4.5 8 2 165 10 425 81 C.sub.40       41      ##STR60##       295 240 5 0.5 6-F H 330 4.5 8 2 160 15 390 74 C.sub.41       42      ##STR61##       206 181 4 0.4 7-Me H 250 4 5.7 1.4 180 30 323 83 C.sub.42       43      ##STR62##       228 181 4 0.4 7-Me H 250 5 6 1.5 180 60 325 81 C.sub.43       44      ##STR63##       214 192 5 0.5 6-Cl 7-Cl 343 2.5 8 2 170 40 314 65 C.sub.44       45      ##STR64##       1770  1250  20 2 H H 2000  3 36 9 180 40 2940  93.6 C.sub.45  46       ##STR65##       274 220 4 0.4 H H 280 4 6 1.5 180 30 338 73 C.sub.46       47      ##STR66##       245 198 4 0.4 7-F H 280 4 5 1.2 180 35 309 71 C.sub.47       48      ##STR67##       221 198 4 0.4 7-F H 280 4 5 1.2 180 30 311 75 C.sub.48       49      ##STR68##       221 198 4 0.4 6-F H 280 3 5 1.2 180 30 332 80 C.sub.49       50      ##STR69##       177 152 3.2 0.3 7-MeO H 230 3 4 1 180 25 245 60 C.sub.50       51      ##STR70##       226 203 4 0.4 7-Me H 280 4.5 4.8 1.2 180 25 319 76 C.sub.51  52       ##STR71##       210 188 4 0.4 6-Cl H 290 3.5 5 1.2 180 35 265 62 C.sub.52       53      ##STR72##       192 171 4 0.4 6-F 7-Cl 290 4 5 1.2 180 40 364 89 C.sub.53       54      ##STR73##       210 188 4 0.4 7-Cl H 290 4 4.8 1.2 180 30 281 67 C.sub.54       55      ##STR74##       184 166 4 0.4 7-CF.sub.3 H 300 3 5 1.2 180 35 343 83 C.sub.55  56       ##STR75##       216 214 5 0.5 5-Cl 7-Cl 290 3 8 2 160 40 316 66 C.sub.56       57      ##STR76##       229 205 4 0.4 8-F H 290 4.5 4 1 180 30 334 77 C.sub.57       58      ##STR77##       249 250 4 0.4 H H 318 4 6 1.5 180 20 382 82 C.sub.58       59      ##STR78##       193 194 4 0.4 7-Cl H 300 3.5 4 1 180 15 307 75 C.sub.59       60      ##STR79##       210 211 4 0.4 7-F H 300 3 4 1 180 20 321 76 C.sub.60       61      ##STR80##       280 250 4.6 0.5 H H 318 3.5 5.6 1.4 180 15 326 70 C.sub.61       62      ##STR81##       198 177 4 0.4 7-F H 250 3 4.5 1.1 180 20 268 72 C.sub.62       63      ##STR82##       244 197 4 0.4 H H 250 4 5 1.2 180 30 317 76 C.sub.63       64      ##STR83##       220 177 4 0.4 7-F H 250 5 4.8 1.2 180 20 275 70 C.sub.64       65      ##STR84##       221 198 4 0.4 6-F H 280 3.5 5.2 1.3 185 25 378 91 C.sub.65       66      ##STR85##        203 182 4 0.4 7-Cl H 280 5 4.8 1.2 185 20 291 72 C.sub.66       67      ##STR86##       229 181 4 0.4 H H 230 3.5 5 1.2 180 15 303 81 C.sub.67       68      ##STR87##       229 181 4 0.4 H H 230 3.5 5 1.2 180 25 318 83 C.sub.68       69      ##STR88##       223 197 4 0.4 H H 250 4 4.4 1.1 180 40 244 61 C.sub.69       70      ##STR89##       225 197 4 0.4 H H 250 4.5 4.8 1.2 180 35 298 77 C.sub.70       71      ##STR90##       336 268 4 0.4 H H 340 5 5 1.2 180 30 457 82 C.sub. 71       72      ##STR91##       298 238 4 0.4 H H 300 4 4 1 180 25 318 65 C.sub.72       73      ##STR92##       303 268 4 0.4 H H 340 6 4 1 180 30 339 65 C.sub.73       74      ##STR93##       303 268 4 0.4 H H 340 4 4 1 180 40 360 67 C.sub.74       75      ##STR94##       330 305 6 0.6 H H 380 4.5 14 3.5 175 60 310 52 C.sub.75       76      ##STR95##       330 305 6 0.6 H H 380 4.5 6 1 150 30 430 72 C.sub.76       77      ##STR96##        670 610 10 1 H H 760 4.5 12 3 160 30 850 71 C.sub.77       78      ##STR97##       303 268 4 0.4 H H 340 4 4 1 180 40 360 67 C.sub.78       79      ##STR98##       193 194 4 0.4 8-Cl H 300 3 4 1 180 20 293 72 C.sub.79       80      ##STR99##       246 248 4 0.4 8-F H 350 3 4 1 180 25 303 60 C.sub.80       81      ##STR100##       562 565 7 0.7 6-F H 800 5 8 2 180 25 862 75.4 C.sub.81       82      ##STR101##       244 245 4 0.4 6-OMe H 370 4 5 1.2 180 30 403 77.4 C.sub.82       83      ##STR102##       497 500 7 0.7 7-F H 708 5 0 9 118 60 679 808 C.sub.83       84      ##STR103##       249 250 4 0.4 8-F H 354 4 4.8 1.2 180 30 395 77.8 C.sub.84       85      ##STR104##       249 250 4 0.4 7-Me H 354 4 4 1 180 35 390 78.0 C.sub.85       86      ##STR105##       199 199 4 0.4 7-CF.sub.3 H 360 3.5 4 1 180 30 376 78.0 C.sub.86  87       ##STR106##       374 375 5 0.5 5-F H 531 3.5 4 1 180 30 367 48.2 C.sub.87       88      ##STR107##       282 250 4 0.4 5-F H 354 4 4.8 1.2 180 50 432 80.3 C.sub.88       89      ##STR108##       200 177 4 0.4 8-F H 250 4 5.6 1.4 180 35 312 87.6 C.sub.89       90      ##STR109##       245 345 4 0.5 5-Cl H 312 3.0 7 2 160 40 312 72 C.sub.90       91      ##STR110##       278 344 4 0.5 5-Cl H 313 2.3 6 2 160 40 268 58 C.sub.91       92      ##STR111##       309 331 4 0.5 5-Cl H 311 3.0 6 2 163 45 346 72 C.sub.92       93      ##STR112##       315 283 5 0.5 5-F H 400 4 4 1 180 40 303 50 C.sub.93

    TABLE 3       ##STR113##       C    Elementary Analysis (%)   Up: Calcd. Cmpd. Solvent for Down: Found N      o. R.sup.1 R.sup.2 R m.p. (°C.) Appearance Crystallin. Molecular      Formula C H N S                        C.sub.2 H H       ##STR114##       296-298 light yellow EtOH C.sub.14 H.sub.9 N.sub.3 SCl 58.8558.86      2.823.22 14.7114.40 11.22 11.22 ClCl 12.4112.34       C.sub.3 H H      ##STR115##       300-301 colorless EtOH C.sub.16 H.sub.10 N.sub.3 F 72.9972.90 3.834.13      15.9615.75  FF 7.227.17       C.sub.7 H H      ##STR116##       304-305 colorless EtOH C.sub.14 H.sub.9 N.sub.3 S 66.9166.94 3.613.55      16.7216.61 12.7612.52       C.sub.8 H H      ##STR117##       225-227 colorless AcOEtn-hexane C.sub.14 H.sub.7 N.sub.3 SCl.sub.2      5      52.522.23 2.202.58 13.1213.00 10.01 9.95 ClCl 22.1422.05  C.sub.9 H H       ##STR118##       286-288 colorless EtOH C.sub.14 H.sub.8 N.sub.3 SCl 58.8558.93 2.822.88 1      4.7114.62 11.22 11.44 ClCl 12.4112.45       C.sub.10 H H      ##STR119##       247-249 colorless EtOH C.sub.16 H.sub.10 N.sub.4 73.1673.34 4.094.43      22.7522.54        C.sub.11 H H      ##STR120##       280-282 colorless EtOHAcOEt C.sub.14 H.sub.9 N.sub.3 S 66.9166.64      3.613.66 16.7216.49 12.7612.60       C.sub.12 H H      ##STR121##       257-258 colorless AcOEt C.sub.14 H.sub.9 N.sub.3 O 71.4871.46 3.863.92      17.8617.79       C.sub.13 H H      ##STR122##       292-293 colorless MeOHAcOEt C.sub.17 H.sub.13 N.sub.3 O 74.1773.80      4.764.90 15.2614.84       C.sub.14 H H      ##STR123##       298-300 colorless EtOH C.sub.16 H.sub.11 N.sub.3 78.3578.06 4.524.47      17.1317.04       C.sub.15 8-Cl H      ##STR124##       315-316 colorless MeOHAcOEt       ##STR125##       52.5752.47 2.392.54 12.7712.88  9.749.68 ClCl 21.5521.55   C.sub.16      8-Cl H       ##STR126##       316-318 colorless EtOHAcOEt C.sub.16 H.sub.9 N.sub.3 ClF 64.5564.54     3      3.05.20 14.1114.10  ClCl 11.9111.83, FF 6.386.27       C.sub.17 H H      ##STR127##       290-291(d) colorless MeOHAcOEt C.sub.14 H.sub.9 N.sub.3 O 71.4871.47      3.864.01 17.8617.80       C.sub.18 H H      ##STR128##       325-326 colorless EtOH C.sub.17 H.sub.13 N.sub.3 S 70.0870.16 4.504.65      14.4214.36 11.0010.87       C.sub.19 H H      ##STR129##       >340 colorless EtOH C.sub.18 H.sub.14 N.sub.4 O.1/2H.sub.2 O 69.4469.47 4      .864.93 18.0017.86       C.sub.20 H H      ##STR130##       291-293 colorless MeOHAcOEt C.sub.16 H.sub.10 N.sub.3 F 72.9972.62      3.833.88 15.9615.83  FF  7.227.28       C.sub.21 H H      ##STR131##       259-260 colorless MeOHAcOEt C.sub.16 H.sub.10 N.sub.3 F 72.9972.94      3.834.16 15.9615.69  FF  7.227.51       C.sub.22 H H      ##STR132##       199-201 colorless AcOEt C.sub.16 H.sub.10 N.sub.3 Cl 68.7068.57      3.603.65 15.0215.04  ClCl 12.6712.82       C.sub.23 H H      ##STR133##       305-306 light yellow EtOHAcOEt C.sub.14 H.sub.8 N.sub.3 SCl 58.8558.58      2.823.16 14.7114.43 11.2210.95 ClCl 12.4112.52       C.sub.24 H H      ##STR134##       233-235 colorless AcOEt C.sub.17 H.sub.13 N.sub.3 O 74.1774.02 4.764.78 1      5.2614.97       C.sub.25 H H      ##STR135##       283-285 colorless EtOH C.sub.15 H.sub.11 N.sub.3 S 67.9067.77 4.184.29      15.8415.59 12.0811.81       C.sub.26 H H      ##STR136##       251-253 colorless AcOEt       ##STR137##       70.3670.29 4.584.61 13.0913.07       C.sub.27 H H      ##STR138##       194-195 colorless EtOH C.sub.16 H.sub.9 N.sub.3 F.sub.2 68.3368.40      3.233.26 14.9415.04  FF 13.5113.46       C.sub.28 H H      ##STR139##       265-267 colorless EtOH C.sub.18 H.sub.16 N.sub.3 O.sub.2.1/8H.sub.2 O      70.2970.26 5.005.07 13.6613.66       C.sub.29 H H      ##STR140##       291-292 colorless EtOH C.sub.18 H.sub.16 N.sub.3 O.sub.2 70.8171.17     4      4.95.94 13.7613.80       C.sub.30 H H      ##STR141##       >340 Yellow DMF C.sub.16 H.sub.10 N.sub.4 O.sub.2.1/4H.sub.2       O 65.1965.48 3.593.74 19.0118.91       C.sub.31 H H      ##STR142##       248-250 colorless EtOH C.sub.16 H.sub.9 N.sub.3 F.sub.2 68.3368.15      3.233.34 14.9414.95  FF 13.5113.62       C.sub. 32 H H      ##STR143##       224-226 colorless EtOHAcOEt C.sub.16 H.sub.9 N.sub.3 F.sub.2 68.3368.63 3      .233.47 14.9514.99  FF 13.5113.72       C.sub.33 H H      ##STR144##       310-311 colorless EtOHAcOEt C.sub.16 H.sub.9 N.sub.3 F.sub.2 68.3368.33 3      .233.49 14.9414.88  FF 13.5113.58       C.sub.34 H H      ##STR145##       326(d) colorless EtOH C.sub.16 H.sub.10 N.sub.3 SCl 60.1059.74 3.363.63 1      4.0213.71 10.6910.61       C.sub.35 7-Cl H      ##STR146##       >310 colorless EtOH C.sub.14 H.sub.8 N.sub.3 SCl 58.8558.61. 2.823.11      14.7114.40 11.2211.11       C.sub.36 7-Cl H      ##STR147##       >315 colorless CHCl.sub.3MeOH C.sub.16 H.sub.9 N.sub.3 ClF 64.5564.67      3.053.32 14.1114.11  ClCl 11.9112.07       C.sub.37 H H      ##STR148##       295-296 colorless EtOHAcOEt C.sub.16 H.sub.11 N.sub.3 S 67.9067.84      4.184.35 15.8415.64 12.0811.97       C.sub.38 7-Cl H      ##STR149##       287-289 colorless EtOH C.sub.15 H.sub.10 N.sub.3 SCl 60.1060.00      3.363.50 14.2013.96 10.6910.60       C.sub.39 7-Cl H      ##STR150##       307-308 colorless EtOH C.sub.15 H.sub.10 N.sub.3 SCl.1/8H.sub.2 O      59.6559.78 3.423.59 13.9114.03 10.6210.20       C.sub.40 8-F H      ##STR151##       >310 colorless EtOHAcOEt C.sub.16 H.sub.9 N.sub.3 F.sub.2 68.3368.20      3.233.48 14.9414.92  FF 13.5113.60       C.sub.41 8-F H      ##STR152##       272-274 colorless EtOHAcOEt C.sub.16 H.sub.10 N.sub.3 SF 63.5963.52     3      3.56.77 14.8314.71 11.3211.02       C.sub.42 7-Me H      ##STR153##       323-326 colorless EtOHAcOEt C.sub.15 H.sub.11 N.sub.3 S.1/8H.sub.2 O      67.3367.18 4.244.51 15.6615.64       C.sub.43 7-Me H      ##STR154##       >315 colorless EtOHAcOEt C.sub.16 H.sub.13 N.sub.3 S 68.7968.52      4.694.91 15.0414.85       C.sub.44 7-Cl 8-Cl      ##STR155##       >300 colorless EtOHAcOEt C.sub.14 H.sub.7 N.sub.3 SCl.sub.2 52.5152.25      2.202.55 13.1313.00 10.01 9.84        C.sub.45 H H      ##STR156##       303-304.5 colorless EtOHAcOEt C.sub.14 H.sub.16 N.sub.4 O 67.1967.25      4.024.22 22.3822.20       C.sub.46 H H      ##STR157##       254-256 colorless AcOEtMeOH C.sub.16 H.sub.12 N.sub.4 O.1/8H.sub.2 O      67.5967.76 4.634.68 21.0220.74       C.sub.47 7-F H      ##STR158##       309-311(d) colorless AcOEtMeOH C.sub.16 H.sub.11 N.sub.4 OF 63.8263.58      3.924.06 19.8419.74       C.sub.48 7-F H      ##STR159##       308-310(d) colorless AcOEtMeOH C.sub.14 H.sub.9 N.sub.4 OF 62.6862.46      3.383.50 20.8820.67       C.sub.49 8-F H      ##STR160##       293-295 colorless AcOEt C.sub.14 H.sub.9 N.sub.4 OF.1/4H.sub.2 O      61.8761.65 3.703.51 20.2820.54       C.sub.50 7-MeO H      ##STR161##       208-282(d) colorless AcOEtMeOH C.sub.14 H.sub.12 N.sub.4       O.sub.2.1/8AcOEt 63.9163.69 4.494.44 19.2319.25  C.sub.51 7-MeO H       ##STR162##       303-305(d) colorless AcOEtMeOH C.sub.15 H.sub.12 N.sub.4.1/8H.sub.2 O      67.4067.36 4.654.67 20.9621.02       C.sub.52 8-Cl H      ##STR163##       310-311(d) light yellow AcOEtMeOH C.sub.14 H.sub.9 N.sub.4       OCl.5/6H.sub.2 O 55.9656.08 3.583.72 18.6418.57  C.sub.53 7-Cl H       ##STR164##       322-325(d) colorless AcOEtMeOH C.sub.14 H.sub.8 N.sub.4 OClF.2/3H.sub.2      O 53.4353.40 2.993.26 17.8017.68       C.sub.54 7-Cl H      ##STR165##       319-321(d) colorless AcOEtMeOH C.sub.14 H.sub.9 N.sub.4 OCl.CH.sub.3 OH 5      6.8756.62 4.134.29 17.6817.54 Cl:Cl: 11.1911.07  C.sub.55 7-CF.sub.3 H       ##STR166##       295-297(d) colorless AcOEt C.sub.16 H.sub.9 N.sub.4 OF.sub.3 56.6056.58 2      .853.05 17.6017.61       C.sub.56 7-Cl-F H      ##STR167##       256-258 colorless EtOH C.sub.14 H.sub.9 N.sub.4 OCl.sub.2 52.6852.40      2.532.62 17.5617.41 Cl:Cl: 22.2222.42       C.sub.57 6-F H      ##STR168##       308-310(d) colorless AcOEtMeOH C.sub.14 H.sub.9 N.sub.4 OF 62.6862.49      3.383.63 20.8820.82       C.sub.58 H H      ##STR169##       271-274(d) colorless AcOEt C.sub.13 H.sub.8 N.sub.4.1/8H.sub.2 O      65.4765.41 3.493.74 23.4923.28       C.sub.59 7-Cl H      ##STR170##       302-306(d) colorless MeOHtCHCl.sub.3 C.sub.13 H.sub.7 N.sub.4       OCl.1/8H.sub.2 O 57.2157.20 2.682.94 20.5320.36   C.sub.60 7-F H       ##STR171##       297-299 colorless AcOEtMeOH C.sub.13 H.sub.7 N.sub.4 OF.1/6H.sub.2 O      60.7060.96 2.873.17 21.7821.73       C.sub.61 H H      ##STR172##       273-274 colorless AcOEt C.sub.14 H.sub.9 N.sub.4 O 67.1967.23 4.024.22      22.3822.20       C.sub.62 7-F H      ##STR173##       328-330(d) colorless AcOEtEtOH C.sub.14 H.sub.9 N.sub.4 OF 62.6862.46      3.383.58 20.8820.67       C.sub.63 H H      ##STR174##       268-269 colorless AcOEt C.sub.15 H.sub.12 N.sub.4 O 68.1768.16 4.574.74 2      1.1921.01       C.sub.64 7-F H      ##STR175##       307-310(d) colorless AcOEtEtOH C.sub.15 H.sub.11 N.sub.4 OF 63.8263.74      3.924.08 19.8419.68       C.sub.65 8-F H      ##STR176##       312-315(d) colorless AcOEtMeOH C.sub.14 H.sub.9 N.sub.4 OF 62.6862.56      3.383.56 20.8820.666       C.sub.66 7-Cl H      ##STR177##       344-347(d) colorless MeOH C.sub.14 H.sub.9 N.sub.4 OCl 59.0658.78      3.183.22 19.6719.44        C.sub.67 H H      ##STR178##       274-275 colorless AcOEtEtOH C.sub.14 H.sub.10 N.sub.4 S.1/6H.sub.2 O      62.3062.56 3.884.12 20.7620.62       C.sub.68 H H      ##STR179##       309-310(d) colorless AcOEtEtOH C.sub.14 H.sub.10 N.sub.4 S.1/6H.sub.2 O 6      2.4362.68 3.874.15 20.8020.89       C.sub.69 H H      ##STR180##       296-298 colorless MeOH C.sub.13 H.sub.9 N.sub.5 O 57.9858.18 4.123.98      26.0125.90       C.sub.70 H H      ##STR181##       290-293(d) colorless MeOH C.sub.12 H.sub.7 N.sub.5 S.H.sub.2       O 53.1353.30 3.343.39 25.8125.54   S:S: 11.8111.69  C.sub.71 H H       ##STR182##       303-305(d) colorless MeOHtAcOEt C.sub.14 H.sub.10 N.sub.4 S 63.1363.29      3.783.80 21.0320.83       C.sub.72 H H      ##STR183##       245-246(d) colorless AcOEt-hexane C.sub.14 H.sub.10 N.sub.4       S.1/8H.sub.2 O 62.6162.89 3.854.00 20.8620.57       C.sub.73 H H      ##STR184##       292-294(d) colorless AcOEtMeOH C.sub.13 H.sub.8 N.sub.4 S 61.8861.94      3.193.30 22.2021.97       C.sub.74 H H      ##STR185##       242-244 colorless AcOEt C.sub.13 H.sub.8 N.sub.4 S.1/5H.sub.2 O      61.0261.27 3.313.57 21.8921.81       C.sub.75 H H      ##STR186##       276-278(d) colorless EtOHAcOEt C.sub.14 H.sub.11 N.sub.6.1/5H.sub.2 O      66.5066.65 4.544.73 27.6927.47       C.sub.76 H H      ##STR187##       263-265 colorless EtOHAcOEt C.sub.14 H.sub.9 N.sub.5 67.4667.56      4.454.74 28.0927.85       C.sub.77 H H      ##STR188##       251-253 colorless EtOHAcOEt C.sub.14 H.sub.10 N.sub.4 O 67.1967.29      4.034.09 22.3922.13       C.sub.78 H H      ##STR189##       242-243 colorless AcOEt C.sub.13 H.sub.8 N.sub.4 S.1/5H.sub.2 I      61.0261.27 3.313.57 21.8921.81       C.sub.79 8-Cl H      ##STR190##       299-302(d) light yellow AcOEtMeOH C.sub.13 H.sub.7 N.sub.4       OCl 57.6857.69 2.602.76 20.6920.53       C.sub.80 8-F H      ##STR191##       308-310(d) colorless MeOHAcOEt C.sub.13 H.sub.7 N.sub.4 OF 61.4161.71      2.773.03 22.0321.91       C.sub.81 8-F H      ##STR192##       308-310.5(d) colorless MeOHAcOEt C.sub.13 H.sub.7 N.sub.4 FO 61.4161.63 2      .773.03 22.0321.86       C.sub.82 8-OMe H      ##STR193##       279-281(d) colorless MeOHAcOEt C.sub.14 H.sub.10 N.sub.4       O.sub.2.1/4H.sub.2 O 62.1062.19 3.933.92 20.69 20.69  C.sub.83 7-F H       ##STR194##       316-319(d) colorless MeOHAcOEt C.sub.13 H.sub.7 N.sub.4 FO.1/8H.sub.2 O 6      0.8861.02 2.853.13 21.8521.77       C.sub.84 6-F H      ##STR195##       329-332(d) colorless MeOHCH.sub.2 Cl.sub.2 C.sub.14 H.sub.10 N.sub.4 FO 6      1.4161.59 2.773.02 22.0321.99       C.sub.85 7-Me H      ##STR196##       294-297.5(d) colorless AcOEt C.sub.14 H.sub.10 N.sub.4 O 67.1967.27     4      4.02.03 22.3822.41       C.sub.86 7-CF.sub.3 H      ##STR197##       324-338(d) colorless MeOHAcOEt C.sub.14 H.sub.7 N.sub.4 F.sub.3 O      55.2755.43 2.312.56 18.4118.40       C.sub.87 9-F H      ##STR198##       277-279 colorless MeOHAcOEt C.sub.13 H.sub.7 N.sub.4 OF 61.4161.51      2.773.02 22.0321.90       C.sub.88 9-F H      ##STR199##       282-284.5(d) colorless MeOHAcOEt C.sub.14 H.sub.8 N.sub.3 FS 62.4462.66 2      .993.26 15.5015.69       C.sub.89 6-F H      ##STR200##       320-322 colorless EtOH C.sub.14 H.sub.8 N.sub.3 SF 62.4462.25 2.993.22      15.6015.36       C.sub.90 9-Cl H      ##STR201##       210-212 colorless MeOH C.sub.13 H.sub.7 N.sub.4 OCl.1/2CH.sub.3 OH      5      56.556.69 3.162.97 19.5520.03  Cl: 12.3712.51       C.sub.91 9-Cl H      ##STR202##       243-245 colorless MeOH C.sub.14 H.sub.8 N.sub.3 SCl 58.8458.79 2.823.02 1      4.7114.86  Cl:Cl: 12.41,12.30, S:S: 11.2210.96  C.sub. 92 9-Cl H       ##STR203##       202-203 colorless MeOH C.sub.16 H.sub.10 N.sub.3 SCl 60.0959.88      3.363.50 14.0214.00  Cl:Cl: 11.83,11.86 S:S: 10.7010.64  C.sub.93 9-F H       ##STR204##       292-294 colorless AcOEtMeOH C.sub.14 H.sub.9 N.sub.4 FO 62.2862.83      3.383.52 20.8820.84

EXAMPLE 94 2-(4-Aminophenyl)-1H-imidazo[4,5-c]quinoline C₉₄ ##STR205##

A suspension of 320 mg of 2-(4-acetylaminophenyl)-1H-imidazo[4,5-c]quinoline C₁₉ in 10 ml of 1N sodium hydroxide is refluxed for 1.5 hours. After the mixture is cooled and neutralized with acetic acid, the resulting white crystals are filtered, washed successively with water and ethanol, and dried to give 195 mg (71%) of C₉₄.

m.p. ca. 340° C. (from ethanol).

Anal. Calcd. (%) (for C₁₆ H₁₂ N₄ 1/8C₂ H₅ OH): C, 73.36; H, 4.83; N, 21.06. Found (%): C, 73.44; H, 4.93; N, 20.95.

EXAMPLE 95 2-(4-methylphenyl)-1H-imidazo[4,5-c]quinoline C₉₅

A suspension of 326 mg of 4-methylbenzoic acid and 318 mg of 3,4-diaminoquinoline A₁ in 10 g of polyphosphoric acid is heated with stirring at 180° C. for 4 hours. The cooled mixture is poured into ice-water and neutralized with aqueous sodium hydroxide. The resulting solid is chromatographed on silica gel with chloroform-methanol (25:1 v/v) as eluent to give 430 mg (83%) of C₉₅ as white crystals.

m.p.: 326°-329° C. (dec.) (from ethanol).

Anal. Calcd. (%) (for C₁₇ H₁₃ N₃.1/3H₂ O): C, 76.96; H, 5.19; N, 15.84. Found (%): c, 76.86; H, 4.84; N, 15.52.

EXAMPLE 96 2-(4-Chlorophenyl)-1H-imidazo[4,5-c]quinoline C₉₆

A suspension of 239 mg of 4-chlorobenzoic acid and 470 mg of 3,4-diaminoquinoline A₁ in 9 g of polyphosphoric acid is heated at 185° C. for 4 hours with stirring under nitrogen. The same work-up as described in Example 95 gives 248 g (59%) of C₉₆ as white crystals.

m.p. 335°-337° C. (dec.) (from ethanol).

Anal. Calcd. (%) (for C₁₆ H₁₀ N₃ Cl): C, 68.70; H, 3.60; N, 15.02; Cl, 12.68. Found (%): C, 68.42; H, 3.71; N, 14.83; Cl, 12.76.

EXAMPLE 97 2-(4-Fluorophenyl)-1-methyl-1H-imidazo[4,5-c]quinoline C₉₇ ##STR206##

To a solution of 390 mg of 4-fluorobenzoic acid in 6 ml of anhydrous hexamethylphosphoramide and 0.6 ml of anhydrous acetonitrile is added dropwise 320 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, a solution of 440 mg of 3-amino-4-methylaminoquinoline A₁₅ in 4 ml of anhydrous hexamethylphosphoramide is added and stirred at 0° C. for 2.5 hours. The same work-up as described in Example 1 gives 750 mg of B₉₇ as a white solid. It is dissolved in 10 ml of acetic acid and refluxed for 1 hour. The mixture is concentrated under reduced pressure and the residue is shaken with ethyl acetate-saturated aqueous sodium bicarbonate. The organic layer is separated, washed successively with water and aqueous sodium chloride, and dried. The solvent is evaporated and the residue is crystallized from n-hexane to give 610 mg (87%) of C₉₇ as white crystals.

m.p.: 185°-187° C. (from ethyl acetate).

Anal. Calcd. (%) (for C₁₇ H₁₂ N₃ F): C, 73.63; H, 4.36; N, 15.15; F, 6.85. Found (%): C, 73.73; H, 4.36; N, 15.15; F, 6.77.

EXAMPLE 98 1-Ethyl-2-(5-methylthien-2-yl)-1H-imidazo[4,5-c]quinoline C₉₈ ##STR207##

To a solution of 270 mg of 5-methylthiophene-2-carboxylic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 215 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, a solution of 320 mg of 3-amino-4-ethylaminoquinoline A₁₆ in 0.5 ml of anhydrous hexamethylphosphoramide is added and stirred at 0°-5° C. for 3 hours. The same work-up as described in Example 1 gives 510 mg of B₉₈ as a white solid. It is suspended in 10 ml of acetic acid and refluxed for 1 hour. The mixture is concentrated and the residue is shaken with ethyl acetate-saturated aqueous sodium bicarbonate. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride, and dried. The solvent is evaporated and the residue is chromatographed on silica gel with chloroform-methanol (20:1 v/v) as eluent to give 380 mg (76%) of C₉₈ as colorless crystals.

m.p.: 205°-206° C. (dec.) (from ethyl acetate).

Anal. Calcd. (%) (for C₁₇ H₁₅ N₃ S): C, 69.60; H, 5.15; N, 14.32; S, 10.93. Found (%): C, 69.66; H, 4.96; N, 14.30; S, 10.88.

EXAMPLE 99 2-(4-Methyloxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₉₉

To a solution of 300 mg of 4-methyloxazole-5-carboxylic acid in 4 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 268 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 340 mg of 3,4-diaminoquinoline A₁ is added and stirred at 0°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 425 mg of 4-amino-3-(4-methylisoxazole-5-ylcarbonylamino)quinoline as crude crystals. It is suspended in 12 ml of Dowtherm A (Dow Chemimical Co.) and refluxed for 2.5 hours. The cooled mixture is diluted with 50 ml of n-hexane and the resulting solid is collected by filtration. It is chromatographed on silica gel with dichloromethane-methanol (20:1 v/v) as eluent to yield a crude solid which is recrystallized from ethyl acetate-methanol, giving 297 mg of C₉₉ as pale yellow crystals.

m.p. 289°-292° C. (dec.).

Anal. Calcd. (%) (for C₁₄ H₁₀ N₄ O.1/8H₂ O): C, 66.59; H, 4.09; N, 22.19. Found (%): C, 66.86; H, 4.18; N, 21.98.

EXAMPLE 100 2-(3-Methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline hydrochloride C₁₀₀

To an ethanolic solution of 300 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ is added ethanolic hydrogen chloride at room temperature. The mixture is evaporated and the residue is washed with acetone to give C₁₀₀ as crystals melting at 248.5°-252° C. (dec.).

Anal. Calcd. (%) (for C₁₄ H₁₁ N₄ OCl.1/3H₂ O): C, 57.45; H, 4.02; N, 19.14; Cl, 12.11. Found (%): C, 57.64; H, 4.27; N, 18.90; Cl, 12.23.

EXAMPLE 101 3-Methanesulfonyl-2-(3-methylisoxazol-5-yl)-3H-imidazo[4,5-c]quinoline C₁₀₁

To a solution of 300 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ in 20 ml of tetrahydrofuran is added 50 mg of 60% sodium hydride in mineral oil and stirred at 75° C. for 2 hours under nitrogen. To the cooled mixture is added dropwise 180 mg of methanesulfonyl chloride and stirred at 0°-5° C. for 2 hours. The mixture is concentrated under reduced pressure and the residue is poured into ice-water. The resulting solid is collected by filtration and chromatographed on silica gel with dichloromethane-methanol (50:1 v/v) as eluent, yielding 159 mg (40%) of C₁₀₁ as white crystals.

m.p. 167.5°-169° C. (dec.) (from ethyl acetate).

Anal. Calcd. (%) (for C₁₅ H₁₂ N₄ O₃ S): C, 54.86; N, 3.68; N, 17.06. Found (%): C, 54.95; H, 3.97; N, 16.79.

EXAMPLE 102 1-Methyl-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₁₀₂

To a solution of 245 mg of 3-methylisoxazole-5-carboxylic acid in 20 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 226 mg of thionyl chloride at -5°-0° C. After stirring at the same temperature for 30 minutes, 330 mg of 3-amino-4-methylaminoquinoline A₁₅ is added and stirred at 0°-5° C. for 5 hours. The mixture is diluted with 50 ml of ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 361 mg (67%) of 4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline. It is suspended in 4 ml of hexamethylphosphoramide and 1 ml of acetic acid and stirred at 180° C. (bath temperature) for 40 minutes. The cooled mixture is poured into ice-water and neutralized with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and chromatographed on silica gel with dichloromethane-methanol (25:1 v/v) as eluent. The product obtained is recrystallized from dichloromethane-methanol to give 294 mg of C₁₀₂ as white crystals melting at 281°-284° C. (dec.).

Anal. Calcd. (%) (for C₁₅ H₁₂ N₄ O) : C, 68.17; H, 4.57; N, 21.19. Found (%): C, 68.29; N, 4.57; N, 21.21.

NMR (CDCl₃ -CD₃ OD): δ2.46(s, 3H), 4.57(s, 3H), 6.99(s, 1H), 7.6-8.7(m, 4H), 9.23(s, 1H).

EXAMPLE 103 2-(Fluorophenyl)-3-methyl-3H-imidazo[4,5-c]quinoline C₁₀₃, 2-(4-Fluorophenyl)-1-methyl-1H-imidazo[4,5-c]quinoline C₉₇ and 2-(4-Fluorophenyl)-5-methyl-5H-imidazo[4,5-c]quinoline C₁₀₄ ##STR208##

To a solution of sodium ethoxide (prepared from 70 mg of metallic sodium and 10 ml of anhydrous ethanol) is added 520 mg of 2-(4-fluorophenyl)-1H-imidazo[4,5-c]quinoline C₃ at room temperature under nitrogen and stirred for 5 minutes. To the mixture is added 0.5 ml of methyl iodide and stirred at 50° C. for 1 hour. The mixture is poured into ice-water and extracted with ethyl acetate. The extract is washed with water and dried. Evaporation of the solvent gives a residue which is chromatographed on silica gel with chloroform-methanol (30:1 v/v) as eluent. The fractions containing the compound with an Rf=0.35 are combined and evaporated to give 90 mg (16%) of 3-methyl derivative C₁₀₃ as colorless crystals.

m.p. 168°-170° C. (ethyl acetate-n-hexane).

Anal. Calcd. (%) (for C₁₇ H₁₂ N₃ F): C, 73.63; H, 4.36; N, 15.15; F, 6.85. Found (%): C, 73.86; H, 4.56; N, 15.13; F, 6.86.

NMR (CDCl₃): δ 4.02(s, 2H), 7.17-8.77(m, 8H), 9.10(s, 1H)

Then evaporation of the combined fractions containing the product with an Rf=0.27 yields 60 mg (11%) of 1-methyl derivative C₉₇ which is identical with the compound obtained in Example 97.

Lastly the combined fractions containing the compound with an Rf=0.12 is evaporated to give 340 mg (62%) of 5-methyl derivative C₁₀₄ as colorless crystals.

m.p. 277°-278° C. (from ethyl acetate-methanol).

Anal. Cald. (%) (for C₁₇ H₁₂ N₃ F): C, 73.63; N, 4.36; N, 15.15; F, 6.85. Found (%): C, 73.64; H, 4.36; N, 15.05; F, 6.76.

NMR (CDCl₃): δ 4.23(s, 3H), 7.03-8.93(m, 8H), 8.56(s, 1H).

EXAMPLE 104 3-Methyl-2-(3-methylisoxazol-5-yl)-3H-imidazo[4,5-c]quinoline C₁₀₅, 1-Methyl-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₁₀₂ and 5-Methyl-2-(3-methylisoxazol-5-yl)-5H-imidazo[4,5-c]quiniline C₁₀₆

To a solution of 450 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ in 39 ml of tetrahydrofuran is added 80 mg of 60% sodium hydride in mineral oil and stirred at 60° C. for 1.5 hours under nitrogen. To the cooled mixture is added dropwise 385 mg of methyl iodide in 2 ml of tetrahydrofuran at 0°-5° C. After stirring at 0°-5° C. for 30 minutes and then at 40° C. for 4 hours, the mixture is evaporated and the residue is chromatographed on silica gel with dichloromethane-methanol (50:1 v/v) as eluent, to give 58 mg (12%) of 3-methyl derivative C₁₀₅ as white crystals.

m.p. 179.5°-182° C. (from ethyl acetate).

Anal. Calcd. (%) (for C₁₅ H₁₂ N₄ O.1/4H₂ O): C, 67.03; H, 4.69; N, 20.84. Found (%): C, 67.16; N, 4.98; N, 20.62.

NMR(CDCl₃ --CD₃ OD): δ 2.46(s, 3H), 4.35(s, 3H), 7.13(s, 1H), 7.6-8.7 (m, 4H), 9.13 (s, 1H).

The further elution with the same solvent yields 42 mg (9%) of 1-methyl derivative C₁₀₂ which is identical with the compound described in Example 102.

Then the eluate with the dichloromethane-methanol (25:1 v/v) affords 322 mg (68%) of 5-methyl derivative C₁₀₆ as white crystals.

m.p.: 308°-309° C. (dec.) (from ethyl acetate-methanol).

Anal. Calcd. (%) (for C₁₅ H₁₂ N₄ O): C, 68.17; H, 4.57; N, 21.19. Found (%): C, 68.14; H, 4.76; N, 21.12.

NMR (CDCl₃ --CD₃ OD): δ 2.42(s, 3H), 4.40(s, 3H), 6.99(s, 1H), 7.6-8.9 (m, 4H), 9.07(s, 1H).

EXAMPLE 105 2-(4-Fluorophenyl)-7-methyl-1H-imidazo[4,5-c]thieno[2,3-b]pyridine F₁ ##STR209##

To a solution of 308 mg of 4-fluorobenzoic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 250 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 358 mg of diaminothienopyridine D₁ is added and stirred at O°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water and dried to yield 630 mg of 4-amino-2-methyl-5-(4-fluorobenzoylamino)thieno[2,3-b]pyridine E₁. It is suspended in 15 ml of polyphosphoric acid and heated at 140° C. with stirring under nitrogen. The cooled mixture is poured into ice-water and neutralized with aqueous sodium hydroxide. The product is extracted with ethyl acetate and the extract is washed with water, dried and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (25:1 v/v) as eluent to afford 457 mg (81%) of F₁ as colorless crystals.

m.p.: 313°-316° C. (from ethanol).

Anal. Calcd. (%) (for C₁₅ H₁₀ N₃ SF): C, 63.58; H, 3.55; N, 14.83; S, 11.31. Found (%): C, 63.32; H, 3.79; N, 14.61; S, 11.09.

EXAMPLE 106 2-(Thien-2-yl)-7-methyl-1H-imidazo[4,5-d]thieno[2,3-b]pyridine F₂ ##STR210##

To a solution of 212 mg of thiophene-2-carboxylic acid in 4 ml hexamethylphosphoramide and 0.4 ml of acetonitrile is added dropwise 188 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at 0°-5° C. for 30 minutes, 269 mg of diaminothienopyridine D₁ is added and stirred at 0°-5° C. for 3 hours. The same work-up as described in Example 105 gives 403 mg of E₂ as crude crystals. It is suspended in 20 ml of Dowtherm A (Dow Chemical Co.) and refluxed for 3 hours under nitrogen. The cooled mixture is diluted with n-hexane and the resulting crystals are filtered. It is chromatographed on silica gel with chloroform-methanol (25:1 v/v) as eluent to give 286 mg (70%) of F₂ as colorless crystals.

m.p.: 284°-287° C. (from methanol-ethyl acetate).

Anal. Cald. (%) (for C₁₃ H₉ N₃ S₂): C, 57.54; H, 3.34; N, 15.48; S, 23.68. Found (%): C, 57.46; H, 3.60, N, 15.39; S, 23.67.

EXAMPLE 107-114

According to the method illustrated by Example 106, Compounds F₃ -F₁₀ are obtained under the conditions shown in Table 4. Table 5 shows the physical properties of these compounds.

                                      TABLE 4                                      __________________________________________________________________________      ##STR211##                                                                     ##STR212##                                                                    __________________________________________________________________________                     Step (1)                                                                                         Yield of                                                                            Reaction                                Ex.             RCO.sub.2 H                                                                         SOCl.sub.2                                                                         HMPAMeCN D    time                                    No.                                                                               R.sup.3                                                                           R         (mg) (mg)                                                                               (ml)(ml) (mg) (hrs.)                                  __________________________________________________________________________     107                                                                               Me                                                                                 ##STR213##                                                                              213  190 4-0.4    270  4                                       108                                                                               Me                                                                                 ##STR214##                                                                              199  160 4-0.4    230  4                                       109                                                                               Me                                                                                 ##STR215##                                                                              199  160 4-0.4    230  4                                       110                                                                               Me                                                                                 ##STR216##                                                                              199  160 4-0.4    230  4                                       111                                                                               H                                                                                  ##STR217##                                                                              214  191 4-0.4    250  3.5                                     112                                                                               H                                                                                  ##STR218##                                                                              214  191 4-0.4    250  3.5                                     113                                                                               H                                                                                  ##STR219##                                                                              215  174 4-0.4    230  3.5                                     114                                                                               Me                                                                                 ##STR220##                                                                              229  230 4-0.4    330  5                                       __________________________________________________________________________                       Step (2)                                                                 Compound                                                                             Yield of    Reaction                                                                            Compound F                                           Ex.                                                                               E     E    Dowtherm A                                                                            time Yields                                                                             Compd.                                           No.                                                                               (mg)  (mg) (ml)   (hrs.)                                                                              (mg)                                                                               No.                                     __________________________________________________________________________              107                                                                               390   370  7.4    2    310 F.sub.3                                          108                                                                               375   350  7      3    310 F.sub.4                                          109                                                                               372   350  7      3.5  305 F.sub.5                                          110                                                                               355   330  6.6    16   250 F.sub.6                                          111                                                                               387   370  7.4    2    315 F.sub.7                                          112                                                                               378   350  7      2    300 F.sub.8                                          113                                                                               300   280  5.6    2    240 F.sub.9                                          114                                                                               514   510  10     1    362 .sup. F.sub.10                          __________________________________________________________________________

                                      TABLE 5                                      __________________________________________________________________________      ##STR221##                                                  F                                                                       Elementary                                                                     Analysis (%)                                                                   Up (Calcd.).             Compd.             m.p.        Solvent for            Down (Found)             No.  R.sup.3                                                                           R          (°C.)                                                                        Appearance                                                                            crystalln.                                                                              Molecular Formula                                                                            C  H  N                  __________________________________________________________________________     F.sub.3                                                                             Me                                                                                 ##STR222##                                                                               295-296                                                                             colorless                                                                             MeOHAcOEt                                                                               C.sub.13 H.sub.9 N.sub.3 S.sub.2                                                             57.54 57.44                                                                       3.34 3.61                                                                         15.48 15.46        F.sub.4                                                                             Me                                                                                 ##STR223##                                                                               277-278                                                                             colorless                                                                             EtOHEt.sub.2 O                                                                          C.sub.14 H.sub.11 N.sub.3                                                      S.sub.2.1/8H.sub.2 O                                                                         58.46 58.49                                                                       3.94 4.12                                                                         14.16 14.56        F.sub. 5                                                                            Me                                                                                 ##STR224##                                                                               268-270                                                                             colorless                                                                             EtOHEt.sub.2 O                                                                          C.sub.14 H.sub.11 N.sub.3                                                                    58.92 58.82                                                                       3.88 3.99                                                                         14.72 14.66        F.sub.6                                                                             Me                                                                                 ##STR225##                                                                               263-266                                                                             colorless                                                                             EtOHEt.sub.2 O                                                                          C.sub.14 H.sub.11 N.sub.3                                                                    58.92 58.73                                                                       3.88 4.11                                                                         14.72 14.81        F.sub.7                                                                             H                                                                                  ##STR226##                                                                               290-293                                                                             colorless                                                                             AcOEtn-hexane                                                                           C.sub.12 H.sub.7 N.sub.3 S.sub.2.1                                             /4AcOEt.1/3H.sub.2 O                                                                         54.72 54.83                                                                       3.41 3.61                                                                         14.73 14.59        F.sub.8                                                                             H                                                                                  ##STR227##                                                                               277-279                                                                             colorless                                                                             AcOEtn-hexane                                                                           C.sub.12 H.sub.7 N.sub.3 S.sub.2.1                                             /8AcOEt       55.94 55.60                                                                       3.00 3.23                                                                         15.65 15.59        F.sub.9                                                                             H                                                                                  ##STR228##                                                                               307-310                                                                             colorless                                                                             AcOEt    C.sub.14 H.sub.8 N.sub.3 SF.1/8AcO                                             Et            62.13 62.32                                                                       3.23  3.35                                                                        14.99 15.25        F.sub.10                                                                            Me                                                                                 ##STR229##                                                                               297-299                                                                             colorless                                                                             AcOEtMeOH                                                                               C.sub.12 H.sub.8 N.sub.4 OS                                                                  56.23 55.99                                                                       3.14 3.35                                                                         21.86              __________________________________________________________________________                                                                 21.70         

EXAMPLE 115 2-Phenyl-1H-imidazo[4,5-d]thieno[3,4-b]pyridine H₁ ##STR230##

To a solution of 187 mg of benzoic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 174 mg of thionyl chloride at 0° C. under nitrogen. After stirring at 0° C. for 30 minutes, 239 mg of diaminothienopyridine D₃ is added and stirred for 3 hours. The mixture is diluted with ice-water and neutralized with aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water and dried to give 280 mg of G₁. It is suspended in 4.2 ml of hexamethylphosphoramide and 1.1 ml of acetic acid, and heated at 170° C. for 30 minutes. The cooled mixture is diluted with ice-water and extracted with ethyl acetate, and the extract is washed with water and dried. After the solvent is evaporated, the residue is chromatographed on silica gel with chloroform-methanol (50:2 v/v) to give 170 mg (51%) of H₁ as colorless crystals.

m.p. 308°-312° C. (dec.) (from ethyl acetate-methanol).

Anal. Calcd. (%) (for C₁₄ H₉ N₃ S.1/3H₂ O): C, 65.35; H, 3.79; N, 16.33. Found (%): C, 65.29; H, 3.73; N, 16.13.

EXAMPLE 116 2-(4-Fluorophenyl)-1H-imidazo[4,5-d]thieno[3,4-b]pyridine H₂

According to the method illustrated by Example 115, 240 mg (50%) of H₂ is obtained from 281 mg of 4-fluorobenzoic acid and 300 mg of diaminothienopyridine D₃.

m.p.: 302°-305° C. (from methanol-ethyl acetate).

Anal. Calcd. (%) (for C₁₄ H₈ N₃ SF): C, 62.44; H, 2.99; N, 15.60. Found (%): C, 62.23; H, 3.26; N, 15.28.

EXAMPLE 117 2-(5-Chlorothien-2-yl)-1H-imidazo[4,5-d]thieno[3,4-b]pyridine H₃

According to the method illustrated by Example 115, 259 mg of H₃ is obtained from 325 mg of 5-chlorothiophene-2-carboxylic acid and 300 mg of diaminothienopyridine D₃.

m.p.: 301°-304° C. (dec.).

Anal. Calcd. (%) (for C₁₂ H₆ N₃ ClS₂): C, 49.39; H, 2.07; N, 14.40. Found (%): C, 49.09; H, 2.17; N, 14.16.

EXAMPLE 118 2-(4-Methoxylphenyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine K₁ ##STR231##

To a solution of 233 mg of 4-methoxybenzoic acid in 4 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 174 mg of thionyl chloride at 0° C. under nitrogen. After stirring at 0° C. for 30 minutes, 230 mg of diaminothienopyridine D₄ is added and stirred at 0° C. for 4 hours. The mixture is diluted with ice-water and neutralized with aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water and dried to yield 348 mg (84%) of J₁. The mixture of J₁ and 6.6 ml of Dowtherm A (Dow Chemical Co.) is refluxed for 2 hours. The cooled mixture is diluted with n-hexane and allowed to stand to give 300 mg (95%) of K₁ as colorless crystals.

m.p.: 285°-287° C. (from ethyl acetate-methanol).

Anal. Calcd. (%) (for C₁₅ H₁₁ N₃ OS.1/5CH₃ COOC₂ H₅): C, 63.48; H, 4.25; N, 14.06. Found (%): C, 63.20; H, 4.38, N, 13.86.

EXAMPLE 119-123

According to the method illustrated by Example 118, Compounds K₂ -K₆ are prepared under the conditions shown in Table 6. Table 7 shows the physical properties of these compounds.

                                      TABLE 6                                      __________________________________________________________________________      ##STR232##                                                                                Step (1)                      Step (2)                             Ex-                               Reac-                                                                              Com-                                                                               Yield                                                                              Dow-                                                                               Reac-                        am-                           Yield                                                                              tion                                                                               pound                                                                              of  them                                                                               tion                                                                               Compound K               ple         RCO.sub.2 H                                                                         SOCl.sub.2                                                                         HMPAMeCN of D.sub.4                                                                         time                                                                               J   J   A   time                                                                               Yield                                                                              Compd.               No.                                                                               R        (mg) (mg)                                                                               (ml) (ml)                                                                               (mg)                                                                               (hr.)                                                                              (mg)                                                                               (mg)                                                                               (ml)                                                                               (hr.)                                                                              (mg)                                                                               No.                  __________________________________________________________________________     119                                                                                ##STR233##                                                                             239  174 4-0.4    230 4.0 365 350 7   1.5 320 K.sub.2              120                                                                                ##STR234##                                                                             308  250 6-0.6    330 3.0 475 400 8   1.5 347 K.sub.3              121                                                                                ##STR235##                                                                             268  250 6.6-0.7  330 3.0 458 440 9   1.5 373 K.sub.4              122                                                                                ##STR236##                                                                             282  250 6-0.6    330 3.5 510 500 10  2   438 K.sub.5              123                                                                                ##STR237##                                                                             260  181 4-0.4    240 3.5 373 350 7   2   310 K.sub.6              __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________      ##STR238##                                            K                                                                       Elementary                                                                     Analysis (%)                                                                   Up (Calcd.).                   Compound       m.p.        Solvent for          Down (Found)                   No.   R        (°C.)                                                                        Appearance                                                                            crystalln.                                                                              Molecular Fomrula                                                                          C  H  N                        __________________________________________________________________________     K.sub.2                                                                               ##STR239##                                                                             334-337                                                                             colorless                                                                             MeOHAcOEt                                                                               C.sub.14 H.sub.8 N.sub.3 CIS.1/4H.sub.                                         2 O         57.93 58.11                                                                       2.95 3.20                                                                         14.48 14.35              K.sub.3                                                                               ##STR240##                                                                             272-278                                                                             colorless                                                                             AcOEt    C.sub.14 H.sub.8 N.sub.3 SF.1/4H.sub.2                                          O          61.41 61.70                                                                       3.13 3.41                                                                         15.35 14.99              K.sub.4                                                                               ##STR241##                                                                             288-293                                                                             colorless                                                                             MeOHAcOEt                                                                               C.sub.14 H.sub.9 N.sub.3 S                                                                  66.91 66.66                                                                      3.60 3.86                                                                         16.72 16.59              K.sub.5                                                                               ##STR242##                                                                             281-285                                                                             colorless                                                                             MeOHAcOEt                                                                               C.sub.12 H.sub.7 N.sub.3 CIS.sub.2.1/6                                         H.sub. 2 O  55.36 55.51                                                                       2.84 3.03                                                                         16.14 15.86              K.sub.6                                                                               ##STR243##                                                                             224-228                                                                             colorless                                                                             MeOHAcOEt                                                                               C.sub.12 H.sub.6 N.sub.3 CIS.sub.2.1/4                                         CH.sub.3 OH 49.07 49.03                                                                       2.35 2.64                                                                         14.01 14.06              __________________________________________________________________________

3,4-Diaminoquinolines

The starting 3,4-diaminoquinolines are prepared by sequential chlorination, amination and reduction of 3-nitro-4-hydroxyquinolines according to literature [G. B. Bachman et al., J. Am. Chem. Soc., 69,365 (1947) and A. R. Surrey et al., J. Am. Chem. Soc., 73,2413 (1951)].

The following table shows their melting points.

    ______________________________________                                         Comp. No. R.sub.1     R.sub.2                                                                               mp (°C.)                                   ______________________________________                                         A.sub.1   H           H      168-170 (dec.)                                    A.sub.2   6-Cl        H      206-209 (dec.)                                    A.sub.3   7-Cl        H      193-195 (dec.)                                    A.sub.4   6-F         H      196-198 (dec.)                                    A.sub.5   7-Me        H      155-158                                           A.sub.6   6-Cl        7-Cl   250-253 (dec.)                                    A.sub.7   7-F         H      185-188 (dec.)                                    A.sub.8   7-MeO       H      136-139 (dec.)                                    A.sub.9   7-CF.sub.4  H      179-181 (dec.)                                    .sup. A.sub.10                                                                           6-F         7-Cl   249-252 (dec.)                                    .sup. A.sub.11                                                                           5-Cl        7-Cl   200-203 (dec.)                                    .sup. A.sub.12                                                                           5-Cl        H      157-159                                           .sup. A.sub.13                                                                           8-F         H      167-169 (dec.)                                    .sup. A.sub.14                                                                           5-F         H        168-169.5 (dec.)                                ______________________________________                                    

REFERENTIAL EXAMPLE 1 3-Amino-4-methylaminoquinoiline A₁₅ ##STR244##

To a suspension of 2.0 g of 4-chloro-3-nitroquinoline in 20 ml of dry ethanol is added 15 ml of 30% methylamine in ethanol. The mixture is stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is triturated with excess water. The resulting crystals are collected by filtration and washed repeatedly with water. The crystals are dried over phosphorus pentoxide in vacuo to afford 1.82 g (93%) of 4-methylamino-3-nitroquinoline.

An analytical sample is recrystallized from ethyl acetate to give yellow crystals melting at 172°-173° C.

Anal. Calcd. (%) (for C₁₀ H₉ N₃ O₂): C, 59.11; H, 4.46; N, 20.67. Found (%): C, 59.33; H, 4.59; N, 20.67.

A suspension of 1.7 g of 4-methylamino-3-nitroquinoline in 75 ml of ethanol is hydrogenated in the presence of 300 mg of 10% palladium on carbon at atmospheric pressure. After hydrogen absorption is complete, the catalyst is removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with chloroform-methanol (2:1 v/v) affords 600 mg (41%) of 3-amino-4-methylaminoquinoline A₁₅ as an oil.

NMR (CD₃ OD): δ 3.05(s, 3H), 7.17-7.50(m, 2H), 7.60-8.15(m, 2H), 8.38(s, 1H).

REFERENTIAL EXAMPLE 2 3-Amino-4-ethylaminoquinoline A₁₆ ##STR245##

To a stirred suspension of 1.40 g of 4-chloro-3-nitroquinoline in 30 ml of dry ethanol is introduced excess amount of gaseous ethylamine at room temperature for 3 hours. Treatment of the reaction mixture as in Example 98 yielded 1.41 g (97%) of 4-ethylamino-3-nitroquinoline. Recrystallization from the ethyl acetate-n-hexane affords yellow crystals melting at 151°-152° C.

Anal. Calcd. (%) (for C₁₁ H₁₁ N₃ O₂): C, 60.82; H, 5.10; N, 19.34. Found (%): C, 60.93; H, 5.07; N, 19.27.

A suspension of 1.34 g of 4-ethylamino-3-nitroquinoline in 40 ml of ethanol is hydrogenated in the presence of 10% palladium on carbon according to the procedure of Referential Example 1, followed by purification to give 0.95 g (82%) of 3-amino-4-ethylaminoquinoline A₁₆ as an oil.

NMR (CD₃ OD): δ1.24(t,3H), 3.35(q,2H), 7.33-7.63(m,2H), 7.77-8.03(m,2H), 8.30(s,1H).

REFERENTIAL EXAMPLE 3 ##STR246## (1) 5-Nitro-2-methylthieno[2,3-b]pyridin-4(7H)-one 2

To a solution of 1.65 g of 2-methylthieno[2,3-b]pyridin-4(7H)-one 1 in 45 ml of acetic acid is added dropwise a solution of 1.24 g of concentrated nitric acid (d=1.38) in 5 ml of acetic acid at 110° C. The mixture is heated with stirring at the same temperature for 10 minutes and left on cooling. The resulting crystals are collected by filtration and washed with ethyl acetate to give 1.07 g (51%) of Compound 2 as pale yellow crystals melting at 280°-282° C. (dec.).

Anal. Calcd. (%) (for C₈ H₆ N₂ O₃ S): C, 45.71; H, 2.87; N, 13.32; S, 15.25. Found (%): C, 45.64; H, 3.42; N, 13.20; S, 15.20.

(2) 4-Chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3

A mixture of 2.26 g of 5-nitro-2-methylthieno[2,3-b]pyridine-4(7H)-one 2 and 10 ml of phosphorus oxychloride is refluxed for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is taken up on ethyl acetate. The organic phase is dried over magnesium sulfate and treated with activated charcoal. The mixture is filtered and the solvent is evaporated in vacuo. The crude product is recrystallized from ethyl acetate-n-hexane to give 1.90 g (68%) of Compound 3 as colorless crystals melting at 96°-98° C.

Anal. Calcd. (%) (for C₈ H₅ N₂ O₂ SCl): C, 42.02; H, 2.20; N, 12.25; S, 14.02. Found (%): C, 41.92; H, 2.48; N, 12.16; S, 14.12.

(3) 4-Amino-5-nitro-2-methylthieno[2,3-b]pyridine 4

To a stirred solution of 1.60 g of 4-chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3 in 50 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 55° C. during 3 hours. The reaction mixture is concentrated in vacuo. The residue is washed with ether and suspended in 7 ml of 1N sodium hydroxide solution with stirring. The resulting crystals are collected by filtration and washed with water and a small amount of ethanol to yield 1.37 g (93%) of Compound 4 as orange crystals melting at 238°-240° C.

Anal. Calcd. (%) (for C₈ H₇ N₃ O₂ S): C, 45.92; H, 3.37; N, 20.08; S, 15.32. Found (%): C, 45.71; H, 3.40; N, 19.84; S, 15.44.

(4) 4,5-Diamino-2-methylthieno[2,3-b]pyridine D₁

A suspension of 1.25 g of 4-amino-5-nitro-2-methylthieno[2,3-b]pyridine is hydrogenated under atmospheric pressure at room temperature in the presence of 360 mg of 10% palladium carbon for 2 hours. After removal of catalyst, the filtrate is concentrated and the residue is triturated with chloroform to give 866 mg (81%) of Compound D₁ as colorless crystals melting at 204°-209° C.

Anal. Calcd. (%) (for C₈ H₉ N₃ S): C, 53.60; H, 5.06; N, 23.44; S, 17.88. Found (%): C, 53.56; H, 5.11; N, 23.24; S, 18.01.

REFERENTIAL EXAMPLE 4 ##STR247## (1) 5-Nitrothieno[2,3-b]pyridin-4(7H)-one 6

To a solution of 3.4 g of thieno[2,3-b]pyridin-4(7H)-one 5 in 105 ml of propionic acid is added 2.79 g of concentrated nitric acid (d=1.38) at 100° C., and then the mixture is stirred at 130° C. (bath temperature) for 1 hour. After cooling the reaction mixture, the resulting precipitate is collected by filtration and washed successively with water, methanol and acetone to afford 3.4 g (77%) of Compound 6 as pale yellow crytals melting at 288°-291° C.

(2) 4-Chloro-5-nitrothieno[2,3-b]pyridine 7

A mixture of 3.4 g of 5-nitrothieno[2,3-b]pyridin-4(7H)-one 6 and 34 ml of phosphorus oxychloride is heated at 115° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 3.51 g (94%) of Compound 7 as crystals melting at 110°-113° C.

(3) 4-Amino-5-nitrothieno[2,3-b]pyridine 8

To a stirred suspension of 3.35 g of 4-chloro-5-nitrothieno[2,3-b]pyridine 7 in 160 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 45°-50° C. during 4 hours. After removal of the solvent, the residue is suspended in water. The solid is washed with water and cold ether, affording 2.65 g (87%) of Compound 8 as crystals. Recrystallization from methanol-ether gives a pure sample melting at 227°-228.5° C.

(4) 4,5-Diaminothieno[2,3-b]pyridine D₂

A mixture of 2.57 g of 4-amino-5-nitrothieno[2,3-b]pyridine 8 and 11.1 g of stannous chloride in 240 ml of ethanol is stirred at 75° C. for 3 hours. The reaction mixture is treated with activated charcoal and filtered. After concentration of the filtrate, the residue is taken up in ethyl acetate and suspended in 185 ml of 5% aqueous sodium bicarbonate. The organic layer is extracted with dilute hydrochloric acid. The aqueous layer is treated with activated charcoal and filtered. The filtrate is basified to pH=10 with 10% sodium hydroxide and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from ethyl acetate-ether to afford 1.65 g (76%) of Compound D₂ as pale yellow crystals melting at 159°-160.5° C.

Anal. Calcd. (%) (for C₇ H₇ N₃ S.1/8H₂ O): C, 50.20; H, 4.36; N, 25.09. Found (%): C, 50.54; H, 4.24; N, 24.95.

REFERENTIAL EXAMPLE 5 ##STR248## (1) 3-Nitrothieno[3,4-b]pyridin-4(1H)-one 10

To a suspension of 4.00 g of thieno[3,4-b]pyridin-4(1H)-one 9 in 120 ml of acetic acid is added 3.00 g of nitric acid (d=1.38). The reaction mixture is stirred at 70° C. for 3 minutes and cooled to room temperature. The resulting crystals are collected by filtration, and then washed with water and methanol-ether, affording 2.51 g (48%) of Compound 10. An analytical sample is recrystallized from dimethylsulfoxide-methanol to give yellow crystals melting at 329°-332° C.

Anal. Calcd. (%) (for C₇ H₄ N₂ O₃ S): C, 42.85; H, 2.05; N, 14.27. Found (%): C, 42.75; H, 2.30; N, 14.13.

(2) 4-Chloro-3-nitrothieno[3,4-b]pyridine 11

A mixture of 3.00 g of 3-nitrothieno[3,4-b]pyridin-4(1H)-one 10 and 9 ml of phosphorous oxychloride is stirred at 105° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with aqueous ammonia and water. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 2.02 g (60%) of Compound 11. Recrystallization from ether-petroleum ether affords colorless crystals melting at 139°-140° C.

Anal. Calcd. (%) (for C₇ H₃ N₂ O₂ ClS.1/8H₂ O): C, 38.77; H, 1.51; N, 12.92. Found (%): C, 38.60; H, 1.55; N, 12.79.

(3) 4-Amino-3-nitrothieno[3,4-b]pyridine 12

To a stirred suspension of 1.25 g of 4-chloro-3-nitrothieno[3,4-b]pyridine 11 in 37 ml of 2-propanol is introduced anhydrous ammonia at room temperature during 3 hours. The mixture is concentrated in vacuo and the residue is suspended in water with stirring. The crystals are collected by filtration, washed with water and dried to give 1.09 g (96%) of Compound 12. An analytical sample is recrystallized from chloroform-methanol, giving yellow crystals melting at 307°-309° C.

Anal. Calcd. (%) (for C₇ H₅ N₃ O₂ S): C, 43.07; H, 2.58; N, 21.52. Found (%): C, 42.93; H, 2.69; N, 21.36.

(4) 3,4-Diamino[3,4-b]pyridine D₃

A mixture of 620 mg of 4-amino-3-nitrothieno[3,4-b]pyridine and 3.59 g of stannous chloride dihydrate in 50 ml of ethanol is stirred at 70° C. for 1 hour. After evaporation of the solvent in vacuo, the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate. The resulting solid is filtered off and washed with ethyl acetate. The combined extracts are dried and evaporated in vacuo. The residue is purified by column chromatography on neutral alumina. Elution with chloroform-methanol (20:1 v/v) affords 490 mg (93%) of Compound D₃, which is recrystallized from ether-methanol to afford colorless crystals melting at 140°-144° C.

Anal. Calcd. (%) (C₇ H₇ N₃ S.2/3H₂ O): C, 47.44; H, 4.74; N, 23.71. Found (%): C, 47.68; H, 4.85; N, 23.24.

REFERENTIAL EXAMPLE 6 ##STR249## (1) 6-Nitrothieno[3,2-b]pyridin-7(4H)-one 14

To a solution of 3.1 g of thieno[3,2-b]pyridin-7(4H)-one 13 in 90 ml of propionic acid is added 1.5 ml of fuming nitric acid at 110° C. with stirring and the mixture is refluxed for 1 hour. The cooled mixture is diluted with 50 ml of ether and the resulting crystals are collected by filtration, washed with water and ether-methanol, and dried to give 3.13 g (78%) of Compound 14. Recrystallization from dimethyl sulfoxide-methanol affords colorless crystals melting at 328°-331° C. (dec.).

Anal. Calcd. (%) (for C₇ H₄ N₂ O₃ S): C, 42.85; H, 2.05; N, 14.27. Found (%): C. 42.88; H, 2.17; N, 14.21.

(2) 7-Chloro-6-nitrothieno]3,2-b]pyridin-7(4H)-one 15

A mixture of 2.7 g of 6-nitrothieno[3,2-b]pyridin-7(4H)-one 14 and 30 ml of phosphorous oxychloride is stirred at 115° C. for 1 hour. The reaction mixture is evaporated to dryness in vacuo. The residue is taken up in dichloromethane, washed successively with aqueous ammonia and water, and then dried over magnesium sulfate. The solvent is removed in vacuo and the crude crystals are purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 2.64 g (90%) of Compound 15. Recystallization from ether gives colorless crystals melting at 124°-125.5° C.

Anal. Calcd. (%) (for C₇ H₃ N₂ O₂ ClS): C, 39.17; H, 1.40; N, 13.05. Found (%): C, 38.96; H, 1.70; N, 12.92.

(3) 7-Amino-6-nitrothieno[3,2-b]pyridine 16

To a suspension of 2.55 g of 7-chloro-6-nitrothieno[3,2-b]pyridine 15 in 130 ml of 2-propanol is introduced excess anhydrous ammonia at 45° C. (bath temperature) during 4 hours and the mixture is evaporated in vacuo. The residue is suspended in water, collected by filtration, and then washed with water and ether to give 2.30 g (99%) of Compound 16. An analytical sample is recrystallized from chloroform methanol, affording yellow crystals melting at 266°-268.5° C.

Anal. Calcd. (%) (for C₇ H₅ N₃ O₂ S): C, 43.07; H, 2.58; N, 21.52. Found (%): C, 43.02; H, 2.76; N, 21.46.

(4) 6,7-Diaminothieno[3,2-b]pyridine D₄

A mixture of 2.3 g of 7-amino-6-nitrothieno[3,2-b]pyridine 16 and 12.5 g of stannous chloride dihydrate in 160 ml of ethanol is heated with stirring at 70° C. for 3 hours. The mixture is evaporated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The resulting solid is filtered off and washed with ethyl acetate. The combined extracts are dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel. Elution with chloroform-methanol (10:1 v/v) affords 1.91 g (97%) of Compound D₄, which is recrystallized from methanol-ether to give colorless crystals melting at 157°-159° C.

Anal. Calcd. (%) (for C₇ H₇ N₃ S.1/4H₂ O): C, 49.54; H, 4.45; N, 24.76. Found (%): C, 49.79; H, 4.35; N, 24.43.

PREPARATION

2-(3-methylisoxazol-5-yl)-1H-imidazol[4,5-c]quinoline: 10 mg

Wheat starch: 48 mg

Magnesium stearate: 2 mg

The above components are mixed with each other to prepare a capsule.

EFFECT OF THE INVENTION

The compounds of the present invention show high affinity to a benzodiazepine receptor. The drugs bound to this receptor are classified as three groups according to the difference of the efficacy. Thus, agonists can be utilized as anxiolytics or anticonvulsants, antagonists can be agents for treating benzodiazepine intoxication and accidental supernumerary uptake, and inverse agonists are expected as psychostimulants.

Experiments for assessing biological activities of the compounds of the present invention are shown below; the number of the test compound nearly corresponds to the number used in Examples and Tables respectively.

EXPERIMENT 1 Binding Test to Benzodiazepine Receptor

This test was carried out in the modified mehtod of Mohler et al. Science, 198, 849-851 (1977).

Receptor preparation was provided from the cerebral cortex of Wistar rats (male, 11 to 13 weeks age). Inhibitory action of the test compound on the specific binding of tritium labeled diazepam to the receptor was evaluated as follows. 2nM tritium labeled diazepam and an aqueous solution of the test compound at 5 or 6 concentrations were incubated with the receptor preparation at 0° C. for 6 minutes. The 50% inhibitory concentration (IC₅₀) was measured by the concentration-response curve.

The inhibitory constant (Ki) was calculated according to the following equation, in which Kd is the dissociation constant of the tritium labeled diazepam and L is the concentration of the labeled ligand.

    ______________________________________                                          ##STR250##                                                                    Compound     Ki      Compound      Ki                                          No.          (nM)    No.           (nM)                                        ______________________________________                                         C.sub.2      0.97    C.sub.58      0.525                                       C.sub.3      15.8    C.sub.59      1.23                                        C.sub.13     8.73    C.sub.60      0.495                                       C.sub.20     27.7    C.sub.61      0.661                                       C.sub.21     1.80    C.sub.67      2.07                                        C.sub.27     1.88    C.sub.68      1.19                                        C.sub.35     19.5    C.sub.70      5.40                                        C.sub.38     15.6    C.sub.71      4.57                                        C.sub.45     0.582   F.sub.2       31.8                                        C.sub.46     0.97    F.sub.7       725                                         C.sub.48     0.907   K.sub.5       10.1                                        C.sub.49     0.237                                                             ______________________________________                                    

Experiment 2 Antagonism of Pentyleneterazole-Induced Convulsion

Agonistic activity was evaluated in this test. Groups of 8-16 male mice were challenged with a dose of 125 mg/kg, s.c. of pentylenetetrazole immediately after intravenous injection of the test compound. The dose required to prevent tonic convulsion and death in 50% of the animal during a 2-h observation period was calculated by the probit method.

    ______________________________________                                         Compound                                                                       No.          ED.sub.50 (mg/Kg)                                                 ______________________________________                                         C.sub.2.sup. 15.97                                                             C.sub.3.sup. 2.31                                                              C.sub.13     4.61                                                              C.sub.20     3.90                                                              C.sub.21     2.05                                                              C.sub.27     1.41                                                              C.sub.38     8.52                                                              C.sub.45     0.71                                                              C.sub.46     1.20                                                              C.sub.48     0.59                                                              C.sub.49     0.32                                                              C.sub.59     3.01                                                              C.sub.61     0.74                                                              ______________________________________                                    

EXPERIMENT 3 Potentiation of Pentylenetetrazole-Induced Convulsion

Inverse agonist activity was evaluated in this test. Groups of 8-16 mice were challenged with a dose of 90 mg/kg. s.c. of pentylenetetrazole (a subconvulsive dose) immidiately after intravenous injection of the test compound. The dose required to produce tonic convulsion and death in 50% of the animals during a 2-h observation period was calculated by the probit method.

    ______________________________________                                         Compound                                                                       No.          ED.sub.50 (mg/Kg)                                                 ______________________________________                                         C.sub.35     1.76                                                              C.sub.58     1.65                                                              C.sub.71     4.18                                                              F.sub.2.sup. 0.13                                                              K.sub.5.sup. 0.54                                                              F.sub.7.sup. 0.50                                                              ______________________________________                                    

EXPERIMENT 4 Traction Test

The modified method of Courvoisier et al. (in "Psychotropic Drugs", ed. by S. Garattini & R. Ducrot. p 373. Elsevier Publishing Co., Amsterdam, 1957) was employed. Groups of 10 mice were made to hang onto a horizontal metal wire (diameter: 1 mm) by grasping and holding with their forepaws 30 minutes after oral administration of the test compound, and the number of mice gripping the wire with hindpaws within 10 sec was counted. The ED₅₀ was calculated by the probit method.

EXPERIMENT 5 Anticonflict Test

The modified method of Geller and Seifter (Psychopharmacol, 1, 482, 1960) was employed. Groups of 5 or more male Wistar rats with well-established conflict behavior were used. A dose was determined as positive when the numbuer of electric shocks (punishment) exceeded more than 12 during a 1 hour observation period starting 30 minutes after oral administration of the test compound. The ED₅₀ was calculated by the probit method.

    ______________________________________                                                      Anti-conflict                                                     Compound     activity    Traction Test                                         No.          ED.sub.50 (mg/kg)                                                                          ED.sub.50 (mg/kg)                                     ______________________________________                                         C.sub.45     2.68        >200                                                  C.sub.48     1.80        >200                                                  C.sub.49     1.19        >200                                                  Diazepam     1.05        5.06                                                  ______________________________________                                    

The pharmacological activities described above suggest that the dissociation of anxiolytic action and muscle relaxation action, both being specific to drugs of benzodiazepine type, was achieved. Thus, the compound of the present invention can be an anxiolytic drug not accompanied with a side effect such as dizziness. 

What we claim is:
 1. A compound of the formula: ##STR251## where R is pyridyl or a 5-membered heterocyclic groiup selected from the group consisting of an isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl or furyl group optionally substituted by one or two members selected from the group consisting of halogen, C₁ -C₅ alkyl and C₁ -C₅ alkoxy,Q is hydrogen, C₁ -C₅ alkyl, C₁ -C₁₀ acyl, C₁ -C₅ alkylsulfonyl or C₆ -C₁₀ arylsulfonyl, ##STR252## R¹, R², R³ and R⁴ each is hydrogen, halogen, C₁ -C₅ alkyl, C₁ -C₅ alkoxy or C₁ -C₅ haloalkyl, Q is present on the nitrogen atom of the 1, 3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5/1, 3b; 2, 3; 3a, 4/or 1, 2; 3a, 3b; 4, 5or its pharmaceutically acceptable acid addition salt.
 2. A compound according to claim 1, in which ##STR253##
 3. A compound according to claim 2, in which R is said 5-membered heterocyclic group optionally substituted by one or two members selected from the group consisting of halogen, C₁ -C₅ alkyl and C₁ -C₅ alkoxy.
 4. A compound according to claim 3, in which the 5-membered heterocyclic group is 2-thienyl.
 5. A compound according to claim 3, in which the 5-membered heterocyclic group is 3-methyl-5-isoxazolyl.
 6. A compound according to claim 4, namely 7-chloro-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline.
 7. A compound according to claim 5, namely 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline.
 8. A compound according to claim 5, namely 7-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline.
 9. A compound according to claim 5, namely 8-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline.
 10. A compound according to claim 1, wherein R is an isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl or pyridyl group.
 11. A pharmaceutical composition comprising a psychotropically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers, diluent and/or excipients.
 12. A method for treating psychotropic disorders which comprises administering an effective amount of the composition of claim 10 to a patient suffering from a psychotropic disorder.
 13. A method for treating psychotropic disorders which comprises administering an effective amount of the compound of claim 2 to a patient suffering from a psychotropic disorder.
 14. A method for treating depression or anxiety which comprises administering a pharmacologically effective amount of the composition of claim 10 to a depressed or anxious patient.
 15. A method for treating depression or anxiety which comprises administering a pharmacologically effective amount of the compound of claim 2 to a depressed or anxious patient. 